The ultimate goal of our program project (PPG) is to investigate the mechanisms and role of hyperglycemia and hyperinsulinemia in explaining the excess risk of cardiovascular disease in people with diabetes. The program provides a multidisciplinary and innovative approach to address the biochemical, molecular and genetic factors involved in the risk of cardiovascular disease (CVD) in diabetes. In the present clinical component of the PPG we have developed a project to study the genetic influences either protecting or enhancing cardiovascular disease in Hispanic families with Non-insulin dependent diabetes mellitus (NIDDM). It is clear from many epidemologic studies that cardiac disease is well underway in people with NIDDM before the clinical diagnosis of diabetes is made suggesting that common genetic factors associates vascular disease with insulin resistance. The Hispanic population is at very high risk for NIDDM and this is likely due to the high prevalence of NIDDM susceptibility in the native American population which contributes significantly to the Hispanic American gene pool. Surprisingly, however, the risk of cardiovascular disease in Hispanic NIDDM patients, while increased over the general population, is not nearly as high as would be anticipated based upon studies in non-Hispanic Caucasian and African American populations. This has led us to the hypotheses that: 1) there are cardiovascular 'protective' genes prevalent in the Hispanic population which reduce the risk of CVD in Hispanic NIDDM patients or 2) there is a form of NIDDM not associated with CVD risk which is common in the Hispanic population and which is genetically distinct from the NIDDM which occurs in other ethnic and racial groups. We propose to test these alternative hypotheses by achieving the following specific aims: 1) To identify two groups of Hispanic NIDDM patients (those with documented coronary artery disease and those without coronary artery disease), and to examine subclinical phenotypes associated with diabetes and atherosclerosis in their adult offspring. The correlation between measures of insulin resistance and measures of atherosclerosis will be compared in the two groups of families and their heritabilities will be assessed; 2) To identify genetic loci which are linked to diabetes-related phenotypes, atherosclerosis-related phenotypes, or both in the Hispanic families described in Specific Aim#1. Three molecular mapping approaches will be used to find linked loci: a) A 10 cm systematic mapping approach will be used to identify regions of the human genome which are likely to contain genes important in these phenotypes; b) Hispanic Caucasian coronary artery disease families and studies of NIDDM families from, and c) Candidate genes and gene regions identified by previous studies in mice models of obesity, diabetes and atherosclerosis which, by virtue of the known syntenic relationships between mice and humans, are likely to reside within the regions identified by the systematic mapping approach will be tested for linkage in these families; 3) When the linkage studies described in Specific Aim #2 identify strong evidence for specific candidate genes, further investigation of these candidates will be performed by single strand conformational analysis to define the molecular basis for their involvement in NIDDM and/or atherosclerosis risk. It will be essential to utilize the GCRC for these studies. The local large population of Hispanics with NIDDM will facilitate successful completion of our project. One exciting new development is the cloning of new gene called uncoupling protein-2 (UCP2). This novel gene linked to obesity and hyperinsulinemia has been cloned by Craig Warden, Ph.D. Our Hispanic population study will provide the first population for genetic analysis of this gene